Atherosclerosis is the leading cause of mortality in the western world. Unlike LDL, HDL levels are inversely correlated with the risk of atherosclerosis. HDL exerts its protective effect through several putative mechanisms, in large part through its ability to promote the so-called reverse cholesterol transport pathway. Atherosclerosis and inflammation share intimate associations and the atherosclerotic process exhibits features of a chronic inflammation. Inflammation is known to significantly alter HDL structure and composition, as well as plasma levels of HDL cholesterol and apolipoproteins, but the underlying mechanisms and the consequences of such changes on atherosclerotic disease are not understood. In studying the impact of HDL on atherosclerosis, it is therefore critical to understand how HDL may be modified as a result of inflammation, both systemically and within the inflammatory microenvironment of the atherosclerotic lesion. The Central Unifying Theme of this program project is an understanding of how inflammation alters HDL structure and metabolism and how such changes influence the development of atherosclerosis. The program comprises three inter-dependent and synergistic projects to address these questions: Project 1, "HDL structure and metabolism during inflammation" (PI, Frederick C. de Beer), will address how inflammation alters HDL remodeling through the actions of secreted phospholipases, SAA and CETP; Project 2, "Inflammation, HDL and Class B Scavenger Receptors" (PI, van der Westhuyzen) will determine how inflammation and SAA impact cellular lipid trafficking by Class B scavenger receptors; Project 3, "Macrophage cholesterol efflux during inflammation" (PI, Nancy R. Webb), will investigate the effect of inflammatory modifications of HDL on macrophage cholesterol efflux and atherosclerotic risk. The major goals of the program are to understand how HDL structure and metabolism are altered during inflammation and to determine how such changes influence HDL's function, particularly its roles in cellular cholesterol efflux and plasma cholesterol transport and its influence on atherosclerosis. The program is expected to make significant contributions towards elucidating how the inflammatory process affects HDL and cholesterol metabolism and the extent to which such effects impact atherosclerotic disease.